Persistent neural activity in the absence of external stimuliin prefrontal neurons is the hallmark of the brain's working memory systems. This property is thought to arise from mutual excitation between and among pyramidal neurons to generate local reverberatory neuronal activity. The failure or deficiency of this Imemory-related activation in vivo is hypothesized to be the cellular basis of cognitive impairment in Ischizophrenia. It has been determined that this process is subject to different influences by specific receptors I responding to dopamine, serotonin, GABA and glutamate. Accordingly, in Project 3, we employ the methods l of single and multiple whole cell recording with synaptic stimulation, pharmacological intervention, and calcium imaging to examine the synaptic and signaling basis of these modulatory influences, focusing on the dopamine system. Specific Aim 1 is directed at examining the differential modulatory influences of D1 and D2 receptors on excitatory transmission between identified neurons in layers 3 and 5, amplifying preliminary evidence of selectivity in different elemental cortical microcircuits (ECMs). Specific Aim 2 carries out similar experiments on synaptic augmentation, a form of short-term synaptic plasticity which recruits neuronal ensembles in specific ECMs and resembles persistent activity in vivo. The objective of Specific Aim 3 is to examine if D1 and D2 receptor effects are mediated by the cAMP-PKA pathway or the PLC-IP3-PKC pathways by selective pharmacological inhibition of PKA and PKC in specific ECMs, as described in Specific Aim 1 and in genetically altered systems as they become available. The advantages of in vitro approaches in providingcell type specific, subcellularly localized, and temporally resolved information which is difficult or impossible to obtain by in vivo methods will therefore complement the findings in other subprojects as well as represent a new and challenging level of analysis of dopamine's involvement in neural function and potential neuropathology.